Mood disorders such as bipolar disorder and major depressive disorder have remarkably high prevalence rates in the United States and worldwide. For a large percentage of patients, outcome measures are quite poor, with high rates of suicide, relapse, and residual symptoms (cognitive and functional impairment, psychosocial disability, and diminished well being). Available treatments for mood disorders are far from ideal -- there is a clear need to develop novel treatments for these devastating disorders. This project is focused on discovering genes, gene expression levels, regulators of gene expression, proteins, and molecular cascades thought to influence the activity of neuronal networks associated with mood regulation. The analyses are done using integrated genomic, proteomic, neurochemical, and behavioral approaches. 1) Roles of microRNAs in gender-specific, stress-induced depression-like behaviors Stress can trigger depression, and depression is more prevalent in woman than men. Our studies address the possible bases at the level of gene regulation for the stress effects and for the sex differences. A novel candidate for regulation of relevant gene expression is microRNAs (miRNAs). MicroRNAs are a class of small, non-peptide-coding RNAs, which bind to target messenger RNAs (mRNAs) in a sequence-selective manner and cause protein translation suppression and mRNA degradation. MiRNAs are known to play critical roles in cellular stress and early development. Accumulating data indicate that miRNAs influence the molecular regulation underlying neuronal development and dendritic spine morphogenesis, synaptic and circuitry plasticity, and circadian rhythms. This raises the intriguing possibility that they may play a role in the biological mechanisms of stress coping, or conversely, maladaptation. We found that chronic restraint stress in mice upregulated several miRNAs, and chronic lithium treatment down regulated several microRNAs. Two of them are common for stress and lithium treatments. We also found that the promoter regions of these two miRNAs contain several glucocorticoid receptor (GR) binding sites and one of the two miRNA genes is located on chromosome X. Therefore, we suspect that one of these miRNAs modulates differential behavioral responses to stress in male and female through a GR-mediated mechanism. We will conduct experiments to examine this hypothesis. 2) A plausible CACAN1C dysfunction in Bipolar Disorder CACNA1C is one of the most promising bipolar risk genes, implicated in several genetic studies. We found that GluR6 knockout (KO) mice, lacking a subunit of the glutamate receptor, are a genetic partial model of mania (Mol Psychiatry, 2009). The mice showed increased levels of a truncated form of CACNA1C. It is known that this truncated form has 10-15 fold increases in calcium current due to lack of c-terminal regulatory domain. We also found that chronic lithium treatment decreased levels of truncated CACNA1C. We further found that Nimodipine, a CACNA1C selective blocker, rapidly alleviated behavioral abnormities of GluR6 KO mice including hyperactivity, increased aggression, increased risk-taking activity, and increased hedonic activity. There are key questions that remain. We will investigate whether truncated CACNA1C per se causes the behavioral abnormalities related to mania. We will also investigate the mechanisms by which GluR6 ablation and lithium treatment regulate levels of truncated CACNA1C.